Vision loss from complications of diabetes is growing at a fierce rate in developing nations around the world and in various populations in our country. A tremendous obstacle to better population-wide prevention is a basic understanding of the early pathogenic mechanisms of the disease. While current approaches are centered on lowering serum glucose, the roles that lipid abnormalities play in this disease have largely been ignored. Seminal large clinical trials have shown a beneficial effect of fenofibrate on retinopathy progression in diabetes. The effect was independent of circulating lipoprotein levels. Fenofibrate is a ligand for peroxisome proliferator-activated receptor ? (PPAR??). This transcription facor acts as a coordinator of cellular responses to nutritional status by binding to various lipids, including phospholipids. An insulin-sensitive catalyst of de novo lipogenesis (DNL), Fatty Acid Synthase (FAS), is required for the provision of specific phospholipid ligands to PPARs in multiple tissues, but has not yet been studied in the retina. This pathway represents a novel potential link between insulin deficiency in Type 1 diabetes or insulin resistance in Type 2 diabetes and progressive damage to the retina in both of these conditions. In this application, we outline a series of experiments in cell culture systems and in animals lacking retinal FAS that are aimed at understanding mechanisms and functions of DNL in the healthy and diabetic retina. We then propose a cross-sectional study to identify people with diabetes at high risk for developing retinopathy through electroretinography, a non-invasive clinical tool that we use extensively at our institution. In patients with this early stage of retinopathy, we will measure erythrocyte phospholipids that have been shown to correlate highly with retinal phospholipids. Together, these studies are aimed at establishing a novel link between abnormalities in systemic and retinal phospholipid metabolism and early functional abnormalities in diabetic retinopathy. We will test the related hypotheses that changes in retinal lipogenesis contribute to diabetic retinopathy and that lipid alterations in peripheral blood are highly correlated with earl ERG changes in the diabetic retina. Towards this goal, we will address the following three aims: (1) To define roles for FAS in regulating retinal lipid metabolism; (2) To determine if targeted deletion of FAS exacerbates retinopathy in diabetic animals; (3) To define specific erythrocyte phospholipid profiles that may be associated with early diabetic retinopathy using a mass spectrometry-based analysis of peripheral blood from human subjects. Through a partnership between endocrinologists and ophthalmologists at our institution, this application has the potential to uncover early pathologic changes in lipid metabolism associated with early diabetic retinopathy, which may have important diagnostic and therapeutic implications. Through our studies, we may deliver blood-based phospholipid biomarkers of early disease that could identify patients who are at high risk for progression. An easily recorded blood-based indicator of early retinopathy may also improve access to care. Prevailing wisdom surrounding prevention of microvascular disease with aggressive glycemic control must be balanced by concerns for increased mortality associated seen with these measures (23, 24). Moreover, because current treatments do not ameliorate diabetic eye disease in many patients (25) and because there are increasing concerns with the safety of currently-used agents (26, 27), lipid-based therapies offer an attractive alternative approach to therapy for this intractable disease.